Therapeutic effect of turmeric on radiodermatitis: A systematic review

Abstract Radiodermatitis (RD) occurs in 95% of cancer patients undergoing radiation therapy. At present, there is no effective treatment for the management of this complication of radiotherapy. Turmeric (Curcuma longa) is a polyphenolic and biologically active natural compound with various pharmacological functions. The aim of this systematic review was to determine the efficacy of curcumin supplementation for reducing RD severity. This review complied with the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) statement. A comprehensive literature search was conducted in Cochrane library, PubMed, Scopus, Web of Science, and MEDLINE databases. A total of seven studies comprising 473 cases and 552 controls were included in this review. Four studies demonstrated that curcumin supplementation had a beneficial effect on RD intensity. These data provide evidence for the potential clinical use of curcumin in supportive cancer care. Further large prospective and well‐designed trials are warranted to exactly determine the “real effective extract, supplemental form and dose of curcumin” for RD prevention and treatment of patients receiving radiotherapy.

cleaning with lukewarm water and lenient soap as well as inhibition of local trauma, there is no established protocol for ameliorating skin radiation toxicity (Campbell & Illingworth, 1992;Lavery, 1995;Roy et al., 2001). Over the last decade, the effects of a wide range of treatments have been suggested for this condition, consisting of moisturizers, anti-inflammatory agents, Aloe vera gel, fatty ointments, silymarin and marigold, curcumin (CUM), and different creams (chamomile, almond, steroid and non-steroid) (Falkowski et al., 2011;Heggie et al., 2002;Pommier et al., 2004).
Various investigations have been performed to assess the efficiency of topical compounds on RD. The findings of a systematic review summarizing five studies demonstrated that deodorant or antiperspirant had no effect on development of RD. Nonsteroidal topical agents had a small positive effect on the incidence of moistdesquamation and treatment of itching (Ginex, 2020). Results from a meta-analysis conducted in 2013 showed that corticosteroids and other conventional topical agents including trolamine, sucralfate, gentian violet, Aloe vera, urea, biafine, mixture of oil and aqueous, vitamin C, and hyaluronic acid were unsuccessful at effective prevention and treatment of RD (Zhang et al., 2013).
CUM derivatives have been found to inhibit amyloid formation during wound healing and has been utilized to treat skin disorders, such as eczema, scabies, acne, and crease skin, as well as preventing chemical and UVinduced skin tumorgenesis in animal studies (Dwivedi & Abu-Ghazaleh, 1997;Dwivedi et al., 2003Dwivedi et al., , 2005. Some studies have also reported the wound healing effect of CUM in combination with other agent, such as ginger and Aloe vera (Bhagavathula et al., 2009;Fray et al., 2004). Results from a recent systematic review has claimed that CUM may have preventive and therapeutic effect on skin redness, transepidermal water loss, and lesions created by RD, psoriasis, and Bowen disease (Barbalho et al., 2021). However, the therapeutic potential of CUR in human studies have been inconsistent (Palatty et al., 2014;Wolf et al., 2018). This review summarized the available evidence support the efficiency of CUM at preventing and treating RD. Estimates of the importance of CUM treatment could improve clinical management, and would assist clinicians to choose better therapeutic strategies for patients.

| Searches
We used multiple databases to identify human intervention studies on the effect of purified CUR or curcuminoids mixture, or standardized Curcuma spp. extracts on RD following Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statements (File S1).
A systematic literature search was performed in Cochrane library, PubMed, Scopus, Web of Science, and MEDLINE limited to English language and published from 1950 to the end of June, 2022. The following keywords were applied for the search separately or together: "curcumin", "curcuma", "turmeric", "curcuma domestica", "Curcuma Longa L", "radiotherapy", "dermatitis", "radiodermatitis" and "radiation dermatitis". Details of the literature search were shown in Figure 1. Also, reference lists of selected articles and other relevant papers were manually searched. Overlapping records were considered just once.
The inclusion criteria were (i) study searched on cancer patients undergoing RT and (ii) evaluated the effect of CUR on RD severity. Any irrelevant records, review articles, meeting abstracts, case reports, in vitro data, and animal studies were excluded. Screening of eligible records and selection of articles to be entered were independently carried out by two expert reviewers and any disagreements in opinion were resolved by consensus with supervisors.

| Data extraction
For each selected study, the following information was retrieved: authors, year, location, design, cancer type, mean receiving radiation dose, number of participants, dose, and duration of intervention as well as assessed measurements and main finding.

| Risk of bias in individual studies
Two reviewers (A.B. and M.A.-Z.) independently assessed the risk of bias among the included studies. We used the Cochrane Collaboration's tool for assessing risk of bias in the included randomized trials, including seven items of selection bias (random sequence generation and allocation concealment), performance bias, detection bias, attrition bias, reporting bias, and other forms of bias. Any disagreements were resolved upon consultation with research team.

| Results of the literature search
According to the search strategy, 438 papers were identified, of which 91% were excluded after removing duplicates and evaluating the titles and abstracts. After assessing the full text of the remaining nine articles, seven articles were selected for comprehensive review ( Figure 1).

| Characteristics of included articles
Finally, seven studies that comprised 473 cases and 552 controls included in this review.

| Outcome
Rao and colleagues compared the preventive effect of VTC (5 g/five times daily) on RD grades with JBO (5 mL/five times daily) as placebo in BC patients under RT. The results indicated that the topical application of VTC delayed  and reduced the intensity of RD during the 5 week intervention (Rao et al., 2017). In an exploration on 50 patients with head and neck malignancy, a significant attenuation in grades of RD were observed in patients using tropical VTC (2 g/five times per day) at all timepoints, including 2 weeks after RD completion versus those received JBO (2 mL/five times per day). Furthermore, the incidence of grade 3 RD was significantly lower in the VTC group (Palatty et al., 2014). Results from double-blinded RCT of 686 BC patients demonstrated that CUM (2.0 g capsules of curcuminoids; three times per day) did not reduce the RDS score, associated pain and symptoms as well as quality of life of patients at the end of trial compared to placebo (Ryan Wolf et al., 2018). Ryan Wolf et al. was also performed a semi-blinded RCT among 171 BC patients to compare the prophylactic potency of three topical-use compounds (CUM, HPR Plus™, and placebo) for reducing RD pain. HPR Plus™ is an FDA-approved medical moisturizer indicated for different types of dermatoses and RD. Mean RDS scales did not significantly differ between study groups (CUM = 2.68; HPR Plus™ = 2.64; placebo = 2.63; p = 0.929) at the end of RCT. But subgroup analysis indicates that CUM therapy may be more effective for reducing score of RDS and pain in patients with high breast separation (≥25 cm) who may have the severe RD (Ryan Wolf et al., 2020). Ryan et al. conducted a double-blind, RCT to evaluate the therapeutic potency of oral CUM (6.0 g daily) to ameliorate the RDS in 30 BC patients undergoing RT without chemotherapy. Analysis demonstrated that CUM reduced RDS score and incidence of moist desquamation versus placebo within radiation. Although, no significant differences were found between the study groups regarding to the redness, associated pain, or symptoms (Ryan et al., 2013).
In another study, 60 cervical cancer patients who received chemoradiotherapy were included for the investigation. Of these, 30 patients received CUM tablets (500 mg BID) for at least 3 months post RT during follow-up and were compared with cases of similar features kept only under observation. Occurrence of RD was significantly lower in CUM arm compared to observation groups (40% vs. 67%; p = 0.038) (Manjunatha et al., 2020).
Belcaro et al. studied the effect of Meriva tablets, a lecithinized formulation of CUM, on side effects of RT among 160 cancer patients. Patients administrated to receive 500 mg Meriva (consist of curcuminoids, soy lecithin and microcrystalline cellulose; ratio 1: 2: 2) or placebo. After 60 days, there was a significantly lower incidence of skin damage was found in curcuminoids arm compared to placebo group (22% vs. 51%, p < 0.05). Meriva also did not show any significant adverse effect, with good tolerability and high compliance (Belcaro et al., 2014).

| Quality appraisal
Six of the included studies were randomized trial. Four (66.6%) studies described the random sequence generation and the allocation concealment in an acceptable manner. Five studies reported acceptable blinding for participants and personnel. Three studies (50%) reported blinding of outcome assessment. The risk of bias summary and risk of bias graph is reported in Figures 2 and 3.

| DISCUSSION
Findings from the present review provides evidence for the beneficial effects of CUM on improving RD in patients with cancer receiving RT (Table 1). Preclinical studies in experimental animal models have shown that CUM supplementation was potentially effective in wound healing in radiation-exposed mice. The process of RD leads to production of free radicals and DNA damages (Schaue et al., 2012;Stone et al., 2003). There is a large body of evidence that indicates that CUM possesses free radical F I G U R E 2 Risk of bias graph: review authors' judgments about each risk of bias item presented as percentages across all included studies.
scavenging activity of reactive oxygen and nitrogen species (Baliga et al., 2013;Gupta et al., 2013). Also, results from in vivo and in vitro studies supported CUMs antioxidants functions and prevention of lipid peroxidation and DNA strands break (Jelveh et al., 2013;Parshad et al., 1998). CUM promoted the rate of wound contraction and reepithelialization of the epidermis, reduced mean healing time, incremental neovascularization, and elevated generation and deposition of collagen at site of injury (Jagetia & Rajanikant, 2004López-Jornet et al., 2011). CUM also protect against ionizing irradiation-associated cataractogenesis in rats (Özgen et al., 2012). Vaughn et al. undertook a systematic review of the effect of both topical and oral CUM on skin health in different disorders such as acne, atopic dermatitis, alopecia, facial photoaging, pruritus, and psoriasis. Of the 18 studies, 10 of them highlighted the ameliorating effect of turmeric in skin disease severity (Vaughn et al., 2016).
Despite its great biological effects, oral CUM administration (up to 8 g/day) has low bioavailability and absorption rate in the gastrointestinal tract, as well as rapid metabolism and elimination from the body. Previously, it has been shown that CUM gel was biologically acceptable to all individuals without any adverse effects or allergic reactions (Anuradha et al., 2015). Only, three studies investigated the effect of turmeric cream or CUM gel on RD, which advantageous effects imply important therapeutic implications. Local delivery provided higher amounts of the active ingredients in the diseased region and prevents probable side effects of systemic administration. Easy to use, non-greasy, patient adherence, prolonged residence duration on the skin, and superior drug release are benefits of topical application. However, topical administration has also been restricted due to the vibrant yellow color pigment of turmeric which is part of the active CUM component, since it may stain the skin.
The small number of clinical trials included may be regarded as a main limitation of the current review of the potential beneficial effects of CUM treatment on RD severity in human cancer patients. Furthermore, included studies were heterogeneous due to their study designs, baseline demographic characteristics, tumor types, mean received radiation dose, supplement form, dose, and duration.

| CONCLUSIONS
This review provides evidence on the potential clinical value of CUM in cancer supportive care. There was no significant difference in outcomes between topical or oral administration. With respect to the prior equivocal findings and that three out the seven studies in the present systematic review did not show a significant benefit of CUM treatment, our findings should be interpreted with caution. An objective scale for RD severity and further investigation for an efficient therapy for RD is needed. Further prospective large and well-designed trials are F I G U R E 3 Risk of bias summary: review authors' judgments about each risk of bias item for each included study. warranted to exactly determine the "real effective extract, supplemental form and dose of curcumin" for RD prevention and treatment in patients receiving RT.